Adjuvant radiotherapy and chemotherapy (RT/chemo) is the standard of care for locally advanced rectal cancer patients. Recently, there has been increased usage of the preoperative RT/chemo sequence since it reduces the bulk of the tumor, enhances local- regional control and facilitates sphincter preservation. Although 9-30 percent of patients achieve a complete response, we cannot definitively differentiate them from those with residual pelvic disease. Through delineation of residual rectal cancer in the bowel wall or pelvic lymph nodes, we anticipate that FDG-PET will improve our selection of patients for sphincter preservation. Furthermore, 11-30 percent of rectal cancer patients receiving pre-op RT/chemo will have extrapelvic metastatic disease at exploration despite a normal preoperative CT scan and CXR. Clearly, patients with an excellent rectal cancer response to preoperative RT/chemo yet with extrapelvic disease should be spared radical abdominal surgery. We hypothesize that PET will alter clinical decision making in patients with locally advanced rectal cancer in terms of: optimal therapeutic strategy and also the ability of PET-FDG to monitor the response of tumors to RT/chemo. We propose a prospective comparison of FDG-PET and CT imaging in T3NO or T3N1 rectal cancer patients undergoing preoperative RT/chemo. Approximately 40 patients per year will be imaged before and after preoperative RT/chemo. PET parameters to be studied include traditional measures such as metabolic rate of tumor expressed as standardized uptake value (SUVavg and SUVmax) and PET derived tumor volume (Size) as well as two novel parameters that we have developed: visual response score (VRS) and the Larson-Ginsberg index (LGI), a measure of the change in total lesion glycolysis. This 3 year study on a sufficient number of patients (n=125) will compare FDG-PET and CT assessment of pathological response to preoperative RT/chemo. Another critical analysis will be the correlation of PET, CT and pathology with recurrence-free interval and disease-specific survival. In a subset of patients (n=30), we will initiate a pilot study to investigate the effect of RT/chemo on glucose transporter (GLUT) expression. Enhanced glycolysis is the basis for FDG uptake in malignant cells and changes in the profile of GLUT transporters may account for the cellular accumulation of FDG in tissues. An analysis of GLUT gene and protein expression will be performed on tumor specimens before and after RT/chemo by RT-PCR and immunohistochemistry, respectively. Alterations in the profile of GLUT expression in response to RT/chemo may provide insight on the effects of RT/chemo on glucose metabolism in rectal cancers. We hypothesize that FDG-PET will provide incremental information to physical exam and CT that will lead to improved individual patient management, specifically, by identifying patients suitable for sphincter preserving rectal cancer surgery as well as those not suitable for radical surgery.